Compounds which inhibit the action of the hormone angiotensin II (AII) and are useful in alleviating angiotensin induced hypertension constitute the subject matter of a tremendous amount of research.
PCT Application, International Publication Number WO 92/00977 published Jan. 23, 1992, discloses 4-alkylimidazole derivatives useful as angiotensin II antagonist antihypertensive agents.
Carini and Duncia, European Patent Application Publication Number (EPA) 0 253 310, published Jan. 20, 1988, discloses a class of imidazole angiotensin II antagonists useful for treatment of hypertension and congestive heart failure. The compounds are active when administered by intravenous injection. Several of the compounds are also orally active. The general disclosure encompasses certain 4-alkyl-2-propyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazoles substituted at the 5-position of the imidazole ring with halogen, nitro, trifluoromethyl or cyano.
Carini, Duncia and Wong, International Application Publication Number WO 89/06233, published Jul. 13, 1989, discloses the same class of imidazole angiotensin II antagonists and also discloses additional imidazole angiotensin II antagonists useful for treatment of hypertension and congestive heart failure. Some of the additionally-disclosed compounds are orally active. The general disclosure of WO 89/06233 encompasses the compounds of this invention, but the compounds of this invention are not specifically disclosed.
PCT Application, International Publication Number WO 91/00277 published Jan. 10, 1991, discloses substitutes imidazoles useful as AII blockers. The compounds describes have activity in treating hypertension and congestive heart failure.
PCT Application, International Publication Number WO 91/00281 published Jan. 10, 1991, describes fused-ring aryl substituted imidazoles useful as AII blockers. The compounds described have activity in treating hypertension and congestive heart failure.
European Patent Application Publication Number 0 434 249 A2 published Jun. 26, 1991 describes benzofuran derivatives useful in treatment or prophylaxis of hypertension and potentially useful for the treatment of cognitive disorders and other diseases such as renal failure, hyperaldosteronism, cardiac insufficiency, congestive heart failure, post-myocardial infarction, cerebrovascular disorders, glaucoma and disorders of intracellular homeostasis.
European Patent Application Publication Number 0 459 136 Al published Apr. 12, 1991 describes benzimidazole derivatives having AII antagonistic activity and antihypertensive activity.
Compounds which inhibit AII such as imidazole carboxylic acid AII blockers can have poor absorption in the gastrointestinal tract. One way in which bioavailability of such compounds might be improved would involve designing a prodrug which would hydrolyze to the corresponding acid under physiological conditions whereby this hydrolysis would occur at some point after the prodrug has been absorbed in the gut thus liberating the parent compound without impairing its pharmacological activity.